Transplanted Neurons Awaken Brain’s Re-wiring Ability

The brain has the power to remodel in response to experience from the outside world. But this ability, known as plasticity, is much greater in certain areas and during certain stages of development. A recent study shows a way to coax the brain into re-routing its circuitry after the window of opportunity was thought to be closed. The finding could be an early step toward new therapeutic approaches to help the brain heal itself from many forms of damage, including visual disorders, stroke, and injury.

Arturo Alvarez-Buylla, Michael Stryker, and colleagues at the University of California, San Francisco, were investigating plasticity in the brain’s visual cortex. Normally this area does not re-sculpt itself through changing experiences in adulthood. Unlike, say, the hippocampus—a memory nexus in which old information can be unlearned as new memories are formed—the visual cortex contains a representation of what the world looks like, where things are, what color they are, whether they are moving or still. Once the brain learns how to see its environment, that information remains stable.

But during a “critical period” of development in the visual cortex—between one and three years of age in humans—a window of plasticity opens up. During this time, if vision is blocked in one eye, the circuits carrying information to the brain will rapidly reorganize, shifting from the non-functioning eye to the one that still works. Babies born with cataracts or other obstructions to one eye can permanently lose their sight in that eye if the problem is not corrected during the critical period.

The importance of being inhibited

Research had shown that certain brain cells called inhibitory neurons play a central role in this brief period of plasticity. These cells produce chemicals that signal other neurons to slow down their firing rate, putting the brakes on neural activity. In animals lacking one such chemical, gamma-amino butyric acid (GABA), the window of plasticity in the visual cortex never opens.

In the late 1990s, Stryker and Takao Hensch, now at Harvard’s Children’s Hospital, Boston, found they could restore the normal critical period in GABA-deficient mice by treating the animals with Valium, the well-known sedative that works by doubling GABA’s effects.

Stryker and other colleagues also showed that in normal mice, strengthening inhibitory neurons with brain-derived neurotrophic factor (a cell-nourishing chemical) could trigger the critical period to begin sooner than usual in the animals’ development.

“We knew it was possible to rescue the plasticity effect in mice with too little GABA, and to speed up its timing in healthy animals,” says Stryker. “That left us with two questions. Could we induce a second critical period in animals who’d had one already? And were the inhibitory neurons doing something in addition to just producing the neurotransmitter—something specific and essential to plasticity?”

The new study, published in the Feb. 26 Science, answers “yes” to both questions. Alvarez-Buylla, Stryker, and colleagues transplanted embryonic inhibitory neurons into the visual cortex of mice between 9 and 11 days old. The mice went through their normal critical period when they were about four weeks old. The researchers induced monocular vision in the mice by experimentally patching one eye for four days. Once the blocked eyes were re-opened, the mice were shown a “noise movie” consisting of rapidly moving images, while the researchers used a technique called transcranial optical imaging to record the responses of the corresponding neurons in the cortex. This procedure was done with four groups of mice at various ages. In the mice whose vision was blocked at 33 days after the procedure, when the embryonic cells were sufficiently matured, a new window of plasticity opened. The firing rate of the neurons in the visual cortex showed a clear shift toward the open eye--the brain was once again re-wiring its connections in response to the impaired vision. Mice at earlier or later stages of development showed a weaker response or no difference at all from untreated mice—indicating that the age of the transplanted neurons, not the age of the host animals—was the determining factor.

The study is the first to induce an extra period of plasticity in the visual cortex by inhibitory neuron transplanation. The finding also argues that something other than the presence of inhibitory neurotransmitters is responsible. As part of the experiment, the team repeated the procedure with mature inhibitory neurons; these transplants, though they did produce GABA, did not produce a new critical period—nor did administration of GABA by itself.

According to Stryker, some unknown step in the embryonic neurons’ development must touch off the period of plasticity—and the mystery holds the key to the therapeutic potential of the research. “Transplanting embryonic neurons into people with brain damage might be a possibility,” Stryker says. “But a better solution would be to figure out what these neurons are doing, then find a way to trigger the process directly. In particular, we want to know what happens when the neurons reach just the right age, what they weren’t doing a week before and won’t be doing a week later.”

Inhibition plays role in visual fine-tuning

To pinpoint the steps through which these developing neurons bring about new plasticity, researchers are examining why inhibitory transmission is so important. This question has led to an even larger one: Why the window of plasticity opens up at all.

“We only know about the critical period as a result of unusual circumstances—from observations of children born with obstructed vision, or from animal experiments,” says Jianhua “JC” Cang of Northwestern University. “But the vast majority of children and animals grow up with both eyes intact. So why should there be this one short time of plasticity in normal visual development?”

In the Jan. 28 Neuron, Cang and colleagues provide some clues to both the purpose of the critical period and the specific role of inhibitory signaling. Their work shows that the brain uses this period to match the circuits leading to the brain from each eye, thus making stereoscopic vision possible.

“Neurons in the sensory areas of the cortex are usually highly specific—they only fire in response to what they’re ‘tuned’ to,” Cang explains. His study shows that during the critical period, visual experience instructs neurons in the binocular circuits to gradually change their tuning until they respond the same way through the left and right eyes.

Cang and Stryker both believe this finding offers a plausible explanation (though not absolute proof) that inhibitory neurons contribute to the matching process. “To achieve balance you have to turn some things up and others down,” Stryker says. “The ‘turning down’ is probably where the inhibitory neurons come in.”

Cang says the therapeutic possibilities of transplanted embryonic neurons may reach beyond the repair of brain injury. “By highlighting some of the sequential steps of brain development, the study by Stryker and co-workers may provide new clues to neurodevelopmental disorders that occur when the timing is thrown off,” he says.